Abstract
The Pierre Robin Sequence (PRS), consisting of cleft palate, glossoptosis and micrognathia, is a common human birth defect. However, how this abnormality occurs remains largely unknown. Here we report that neural crest cell (NCC)-specific knockout of transferrin receptor (Tfrc), a well known transferrin transporter protein, caused micrognathia, cleft palate, severe respiratory distress and inability to suckle in mice, which highly resemble human PRS. Histological and anatomical analysis revealed that the cleft palate is due to the failure of palatal shelves elevation that resulted from a retarded extension of Meckel's cartilage. Interestingly, Tfrc deletion dramatically suppressed both transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling in cranial NCCs-derived mandibular tissues, suggesting that Tfrc may act as a facilitator of these two signaling pathways during craniofacial morphogenesis. Together, our study uncovers an unknown function of Tfrc in craniofacial development and provides novel insight into the etiology of PRS.
Highlights
Neural crest cells (NCCs) are highly pluripotent stem cell populations that arise from the neural folds and migrate extensively to different regions, where they differentiate into a broad range of cell types to build up various structures
We propose that Transferrin receptor (Tfrc) is a facilitator of TGF-β and bone morphogenetic protein (BMP) signaling and Tfrc-mediated activation of these two signaling pathways is essential for craniofacial morphogenesis
Sections from embryonic day 9.5 (E9.5) wild-type embryos were labeled with Tfrc and transcription factor activator protein 2α (AP-2α) antibodies, a marker for premigratory and migratory NCCs.[25,26]
Summary
Neural crest cells (NCCs) are highly pluripotent stem cell populations that arise from the neural folds and migrate extensively to different regions, where they differentiate into a broad range of cell types to build up various structures. Histological and anatomical analysis revealed that cleft palate results from the failure of palatal shelves elevation, the failed palatal shelves elevation is due to retarded extension of Meckel’s cartilage that is essential for Abbreviations: AP-2, adaptor protein 2; BA, branchial arch; BMP, bone morphogenetic protein; BrdU, 5-bromo-2ʹ-deoxy-uridine; CNCCs, cranial neural crest cells; E, embryonic day; FNP, frontonasal prominence; KO, knockout; MEE, medial edge epithelium; NCCs, neural crest cells; P, postnatal day 0; Ppmx, palatal process of maxilla; Pppl, palatal process of palatine; PRS, Pierre Robin Sequence; Tfrc, transferrin receptor; TGF-β, transforming growth factor-β. The ablation of Tfrc in NCCs significantly suppressed transforming growth factor-β (ΤGF-β) and BMP signaling in NCCs-derived mandibular tissues Based on these data, we propose that Tfrc is a facilitator of TGF-β and BMP signaling and Tfrc-mediated activation of these two signaling pathways is essential for craniofacial morphogenesis
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